1. Field of the Invention
The present invention relates generally to the design of an improved delivery apparatus for applying two component fibrinogen/thrombin tissue sealants. More particularly, this invention is directed to the design of an apparatus that is easy to use and to fill, that allows accurate dispensing of small volumes and rapid dispensing of large volumes of tissue sealant, that allows minimal dilution of the fibrinogen component, and that ensures thorough mixing of the two sealant components, thus promoting rapid coagulation with a minimal amount of thrombin to produce a homogeneous tissue sealant.
2. Discussion of the Background
Clotting of blood in vivo takes place by conversion of the soluble plasma protein fibrinogen into fibrin, which spontaneously polymerizes into an insoluble gel matrix which may attach to adjacent tissue. The gel matrix stops bleeding and stabilizes structures. Thrombin catalyzed conversion of fibrinogen to fibrin can be reproduced in vitro and has great utility for adhering tissues and achieving hemostasis. Such fibrin sealants and fibrin glues are available commercially and are also made in blood processing laboratories. Preparation and use of fibrinogen-based sealants have been extensively reviewed.sup.1.
Fibrin sealants, fibrin glues and adhesives based on combining fibrinogen-containing solutions with thrombin-containing solutions are used to reduce bleeding and restore hemostasis during surgical procedures. They have been known and in use for many years during which technology has evolved significantly. For example, fibrin clots can be made using different concentrations of fibrinogen in conjunction with the thrombin solution.sup.2. Subsequent developments in technology include cryoprecipitate fibrinogen.sup.3. Concentrated plasma can be used as the fibrinogen component in fibrin sealants.sup.4.
Similarly, various types of applicators for fibrin glue are known.sup.5. An optimal design is not obvious because of the chemical and biological properties of the liquid resulting from combining fibrinogen and thrombin solutions. Because of the rapid polymerization upon intimate interaction of fibrinogen and thrombin, it is important to keep separate these two blood proteins until application to the site of use. In practice, the two components are typically dispensed simultaneously from separate syringes and brought together by means of an applicator manifold.
For example, one syringe-type apparatus for applying a tissue adhesive includes a plurality of standardized one-way syringe bodies of synthetic material.sup.6. Each syringe body accommodates a plunger and ends in a conus. The apparatus also includes a means for holding together the various syringe bodies, a guide rod, common actuating means and a head collecting the coni of said syringe bodies. This design, however, does not appear prevent clogging when flow of materials is interrupted during the course of its use in applying these materials to a surface. The connecting head brings the two materials together and the materials then travel together to a single mixing needle. Because of the rapid coagulation of the materials on mixing, this arrangement facilitates clogging of the apparatus (and in particular, the head or manifold), thus rendering the apparatus unusable.
In a later design, a medicinal gas is used to clear the mixing needle and address the clogging problem.sup.7. It is acknowledged that the tissue adhesive may set in the mixing needle in case of an interruption of the flow of the components during application or when using long and thin mixing needles. Consequently, the mixing needle must be exchanged immediately (e.g., upon interruption of use). However, from a practical perspective, the use of a medicinal gas is not suitable for most situations.
Similar arrangements/designs may be subject to the same deficiency, clogging. One design makes use of a ribbon-like separation means to confine clogging to a disposable tip.sup.8. Another design has the useful feature of specifying that the two syringes have different cross sections.sup.9. This arrangement includes a plurality of syringe bodies having equal effective strokes, each of the syringe bodies ending in joining pieces; a piston in each syringe body for commonly actuating them; and a connecting head attached to the joining pieces of the syringe bodies and provided with a separate conveying channel for each of the components to be applied. In this design, one of said syringe bodies has a cross-sectional area that is two to nine times larger than the cross-sectional area of the remaining syringe bodies. The larger syringe body contains an adhesive protein solution having a fibrinogen content of from 3 to 12%.
One reason for this arrangement/design is that the strength of the sealant is proportional to the fibrinogen concentration. Further, since cryoprecipitate fibrinogen is not very soluble a smaller volume of thrombin solution is useful in making a gel with greater adhesive and tensile strength.
An alternative embodiment that may help to minimize the clogging problem arranges for the two components to meet and mix within a disposable mixing tip.sup.10. This apparatus includes a plurality of distinct, elongate chambers containing fluids, each chamber including a piston for forcibly ejecting the fluid therefrom through a tapered nozzle; needle means having a corresponding plurality of interior conduits for dispensing fluid from said nozzles; lock means including a ridge projecting about an exterior surface of each tapered nozzle; and releasable retaining means comprising a separable needle and a releasable retaining means comprising a separable needle block having a fluid conduit with an interior groove for engaging a corresponding nozzle ridge and means for retaining associated needle means in sealing relationship with the chamber nozzles and the fluid conduits.
The apparatus, however, may be inappropriate for use in delicate microsurgical applications. Separation of the two components in separate channels in the mixing tip is effective but not optimal.
It is known that the tensile and adhesive strengths of fibrin sealants are best if the two solutions are mixed well, preferably rapidly to homogeneity.sup.11. One apparatus which addresses the clogging problem prevents commingling of the two sealant components until they reach the treatment site.sup.12. This apparatus, however, may not provide thorough and adequate mixing of the two solutions. The same limitation is found in an endoscope design.sup.13.
Moreover, all of the heretofore referenced patents similarly fail to effectively address the issue of providing for thorough mixing of the sealant components during application, particularly if the apparatus is designed to overcome the clogging problem. This has two undesirable consequences: (1) the resultant gel is inhomogeneous and not as strong as that resulting from homogeneously mixed solutions and (2) more thrombin may be required to ensure rapid gelling. Risks associated with use of bovine thrombin make it undesirable to use excessive amounts. The U.S. Food and Drug Administration has expressed concern over coagulopathies associated with immunological reactions to commonly used bovine thrombin preparations.sup.14. The risk of zoonotic disease transmission has prompted the United Kingdom, Ireland and France to ban the use of bovine thrombin.
A method for conversion of autologous fibrinogen to non-cross-linked fibrin II or incomplete fibrinogen cleavage products (fibrin I or des BB fibrin, having one or the other of the two fibrinopeptides intact) using an insolubilized enzyme addresses a need for a thrombin-free fibrin glue.sup.15. The resulting unstabilized gel is dissolved by pH adjustment, separated from the insolublized enzyme, then mixed with buffer to restore conditions favorable to the repolymerization of the solubilized fibrin monomer solution, thus avoiding the addition of any soluble foreign animal protein (thrombin) to effect gelation of the sealant. A similar single protein solution method uses a mixture of thrombin and fibrinogen with an agent that inhibits the clotting activity of thrombin.sup.16.
Limitations of these two methods include their multi-step nature and the consequent expense and time required to carry out the processes. Additionally, the molecular structure and physical and adhesive properties of the resultant gels are not likely to be equivalent to those of naturally formed clots.sup.17.
Yet another limitation of previous applicator designs is that depressing syringe plungers may render accurate dispensing of small volumes of sealant (e. g., single drops) difficult. Proposed solutions to this difficulty include a dispenser with a push button actuator.sup.18 and a device using a lever and ratchet and pawl mechanism.sup.19 to dispense sealant components by pressure so that small volumes can be dispensed during delicate operations such as otological surgical procedures. Both of these devices are limited by the inability to rapidly dispense larger volumes of sealant when required, thus falling short of practical volume flexibility needs.
The use of unequal amounts of solutions within the syringe bodies dispensed simultaneously advantageously allows for minimizing dilution of the fibrinogen containing solution by the thrombin solution. However, filling the separate compartments with the respective sealant components and assembling the mechanical components comprising these devices can be complicated and time consuming.
One applicator, designed to produce a mist of mixed components.sup.20, is similarly complicated to assemble and use. If care is not taken in assembly of the device, misalignment of the two syringes with respect to the applicator device and incomplete sealing of the syringe Luer ports into the docking ports of the applicator manifolds may occur. In addition, mixing takes place in a spray head which may clog after use.
Alternatively, the two components of a fibrinogen-based tissue sealant may be applied as separate aerosols and mixed in the field.sup.21,22. These devices may not allow for adequate mixing of the two sealant components, Consequently, greater amounts of thrombin and inferior gels may be produced, a problem inherent in field mixing.